This is a competing renewal grant application requesting continuing support of the project DA017618 Mouse model of HIV-1 infection and drug addiction. In the first funding cycle we accomplished our overall objective to develop a model of HIV-1 infection in conventional mice and applied it for studies on HIV-1 neuropathogenesis. Infection of mice induces lasting cognitive deficits that develop despite effective protective anti-HIV-1 immunity and in the absence of overt neuropathology or viral encephalitis. We believe these results establish an animal model of milder forms of HIV-1 Associated Neurocognitive Disorder (HAND). We hypothesize that the etiology of HAND is different from etiology of HIV induced immunodeficiency as indicated in HAND observed early in viral infection in the presence of an intact immune system. We propose that early HAND (E-HAND) is driven by responses of macrophages to HIV-1 infection but its extent is limited by effective antiviral responses. The damage to the nervous system resulting from initial HIV-1 infection in the brain may set the conditions for rapid progression of HAND after the immune system weakens and may represent early brain injury that is poorly responsive to antiretroviral treatments later in infection. Four Specific Aims are proposed to test these hypotheses: In Aim 1, we will define will define overall parameters of cognitive/behavioral deficits (E-HAND) in EcoHIV infected immunocompetent mice in relation to the progress of infection. In Aim 2, we will define the period of HIV-1 infection when the brain is most vulnerable to the induction of E-HAND; these studies will test the hypothesis that adaptive antiviral responses to systemic EcoHIV infection limit EcoHIV replication in the brain but not E-HAND. In Aim 3, we will test the hypothesis that infiltration of macrophages from the periphery, rather that expansion of virus in the brain, is responsible for the induction of E-HAND under intact immune system. In Aim 4, we will determine whether induction of immunodeficiency or overt neuropathology in infected animals with E-HAND promotes transition to more severe forms of HAND and whether E-HAND and severe HAND can be reversed by antiviral treatment. These studies will evaluate the possibility that some neurological damage caused by early HIV infection in the brain might be irreversible. We believe that the proposed studies are important in light of the increasingly wide use of antiretrovirals which prevent progression to AIDS but fail to prevent certain forms of HIV-1 neurocognitive disease. Our long-range goal is to employ our model to determine the biological interactions between the behavioral defects experienced during early HIV-1 infection and the injuries inflicted by illicit drug abuse to devise interventions that will preserve cognitive and motor function.